Ongoing Challenges in Treating Mantle Cell Lymphoma
Insights From: Brad Kahl, MD, Washington University School of Medicine; John P. Leonard, MD, Weill Cornell Medical Center
Brad S. Kahl, MD: Where we really want to go in mantle cell lymphoma is personalized therapy. Could we take a patient’s diagnostic material, their biopsy, and do some sort of molecular characterization of it, sequencing of the genome so it would tell us how well standard treatments might work for them? Or perhaps they are a better candidate for a novel targeted agent. That’s really the goal in mantle cell lymphoma, as it is in all cancers. We are not there yet. That’s going to require quite a bit of research and work over the next few years to make that a reality.
John P. Leonard, MD: In illnesses and cancers that have a chronic nature to them, and you have multiple therapies that can work over time, 1 question that comes up is, do you give those therapies in sequence or do you give them in combination? The advantage of giving the treatment in sequence is that there’s less toxicity. Obviously, when you give them in combination, you’re going to have more toxicity because the patient is getting 2 drugs with side effects at the same time, but then they have greater efficacy, particularly if there’s synergy between the 2 agents. So, that’s an important question in mantle cell lymphoma because we have lots of active agents. Do we add our new drugs, say ibrutinib or lenalidomide, to chemotherapy, such as bendamustine/rituximab, at the time that we’re giving them? Do we give them as a maintenance? Or do we give them at the time of relapse? Should we give a patient, say, BR and then give them later, at the time of relapse, lenalidomide or ibrutinib?
And so, there’s a lot of philosophy on that. I think that right now, we don’t have the answer to those issues. We’re in clinical trials, where we’re combining multiple novel agents. We have clinical trials combining ibrutinib with bendamustine and rituximab. We have clinical trials combining lenalidomide with rituximab as a maintenance. And as we have those results, we’ll be able to better assess what the efficacy and toxicity is of those combinations.
Brad S. Kahl, MD: The challenge in mantle cell lymphoma is to make those remissions last longer. If you’re a young patient who gets intensive therapy, the average length of the first remission is in the 7-year range. If you’re an older patient who gets a nonintensive strategy, the average length of the first remission is in the 4-year range. So, what are you going to do next? That’s when you can go to these novel targeted agents. But most of these have response durations in the 12- to 18-month range. You can run out of your ammunition in mantle cell lymphoma pretty quickly, and so keeping people in remission with mantle cell lymphoma is the big challenge.
I think the future is going to be to take these novel targeted agents and combine them with standard immunochemotherapy to see if we can get a better response to the initial frontline therapy and/or to take novel targeted agents and combine them together in either the relapsed setting or the frontline setting. For example, ibrutinib is very active in mantle cell lymphoma. Venetoclax, which is a small molecule BCL2 inhibitor, is very active in mantle cell lymphoma. And so, ibrutinib/venetoclax is a very attractive combination of 2 targeted agents that hopefully will be synergistic in mantle cell lymphoma.
John P. Leonard, MD: One of the issues in mantle cell lymphoma is the fact that we are, unfortunately, not curing most of these patients. We’re trying to extend their life, we’re trying to improve their quality of life. And so, clearly, an agent that is more effective and makes people live longer has value even if it has side effects and toxicity. However, if the treatment does not make people live longer—it’s just extending a remission, but that comes at a cost of toxicity and quality of life—then the trade-off for the patient may not be a favorable one that wants the patient to be treated more aggressively. So, clearly, as in indolent lymphomas, we need to be focused on quality of life as one of our endpoints. And one might even argue that in mantle cell lymphoma—where, again, patients are living chronically with the disease—that short of a major overall survival benefit, the goal of therapy should really be improving the patient’s quality of life and minimizing side effects from the disease and from the treatment while trying to keep them in remission as well as we can for as long as we can.